110: Rare coding variants implicate STAG1 and ZNF136 in schizophrenia

Chick SL et al et al., Nature Communications - Largest exome-sequencing meta-analysis to date (28,898 cases, 103,041 controls, 3,444 trios) identifies STAG1 and ZNF136 at exome-wide significance and six additional genes at FDR<5%, highlighting roles for chromatin organisation and GABAergic signalling. Key terms: schizophrenia, rare coding variants, STAG1, SLC6A1, whole-exome sequencing. Study Highlights: The authors generated a new exome-sequenced case-control sample (4,650 cases, 5,719 controls) and meta-analysed published data for a total of 28,898 cases, 103,041 controls and 3,444 trios. They report exome-wide significant enrichment of rare PTVs and damaging missense variants in STAG1 and PTVs in ZNF136, plus six genes at FDR<5% including SLC6A1 and KLC1. SLC6A1 and KLC1 associations are driven by damaging missense variants, and STAG1 and KLC1 overlap loci from schizophrenia GWAS. Several implicated genes show pleiotropic rare-variant enrichment in developmental disorders, autism and epilepsy. Conclusion: STAG1 and ZNF136 are implicated in schizophrenia at exome-wide significance and six additional genes at FDR<5%, supporting disrupted chromatin organisation and altered GABAergic/neural transport pathways in disease etiology. Music: Enjoy the music based on this article at the end of the episode. Article title: Whole-exome sequencing analysis identifies risk genes for schizophrenia First author: Chick SL et al Journal: Nature Communications DOI: 10.1038/s41467-025-62429-y Reference: Chick SL et al., Whole-exome sequencing analysis identifies risk genes for schizophrenia. Nature Communications (2025). DOI: 10.1038/s41467-025-62429-y License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support: Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/whole-exome-sequencing-identifies-new-schizophrenia-risk-genes QC: This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-18. QC Scope: - article metadata and core scientific claims from the narration - excludes analogies, intro/outro, and music - transcript coverage: Audited transcript sections covering study design and sample, gene discoveries (STAG1, ZNF136; six additional genes), mechanistic biology (cohesin/chromatin, GABA signaling), convergence with common-variant signals, NRXN1 CNV locus, pleiotropy, and limitations. - transcript topics: Study design and new exome sequencing sample; Gene discovery: STAG1 and ZNF136 (exome-wide); Six additional genes at FDR<5%: SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, CGREF1; Damaging missense variants driving SLC6A1 and KLC1 (MPC > 2); Convergence of rare- and common-variant signals at STAG1 and KLC1; NRXN1 PTV enrichment and CNV locus overlap QC Summary: - factual score: 10/10 - metadata score: 10/10 - supported core claims: 7 - claims flagged for review: 0 - metadata checks passed: 4 - metadata issues found: 0 Metadata Audited: - article_doi - article_title - article_journal - license Factual Items Audited: - STAG1 exome-wide significance for rare PTVs and damaging missense (MPC>2) - ZNF136 exome-wide significance for rare PTVs - Six additional genes at FDR<5%: SLC6A1, PCLO, ZMYND11, BSCL2, KLC1, CGREF1 - SLC6A1 and KLC1 associations driven by damaging missense variants (MPC>2) alone - NRXN1... Chapters (00:00:00) - The genetics of schizophrenia (00:01:21) - Celebrating the genetic puzzle of schizophrenia (00:05:28) - The Bigger Study of Schizophrenia (00:08:29) - Schizophrenia genetics: The gold standard (00:10:59) - The convergence of genetic signals for STAG1 and KLC1 (00:12:21) - Scratching the genetic map of schizophrenia (00:16:49) - Schizophrenia genetic diversity and how to spot it